Project Summary Coronary heart disease (CHD) presents an enormous physical, social and economic burden, and this burden may be exacerbated in the estimated 6.2 million and rapidly growing number of CHD patients who are obese. Cardiac rehabilitation programs have the potential to significantly reduce morbidity and mortality in CHD patients. However, the efficacy of exercise-based cardiac rehabilitation for improving exercise capacity and CHD risk factors is blunted in CHD patients with obesity. As such, a large proportion of these patients are not experiencing optimal treatment benefits with the current standard of care. Cardiac rehabilitation programs are currently limited by their short duration (3 months), inadequate focus on obesity treatment (nutrient vs. caloric intake), and inability to produce meaningful weight loss (<3%). While multiple lines of evidence suggest that a strategy such as caloric restriction that produces weight and fat loss will improve outcomes in CHD patients with obesity, a definitive randomized clinical trial using evidence-based approaches to weight loss in the cardiac rehabilitation setting is needed. The primary goal of this study is to test the main hypothesis that adding a novel 6-month behavioral weight loss intervention (i.e., calorie-restricted diet with meal replacements) to exercise-based cardiac rehabilitation will lead to greater improvements in exercise capacity, arterial function, body composition and fat distribution, quality of life, CHD risk factors, and inflammation. We will also examine whether short-term benefits are sustained long-term by reassessing outcomes 12 months after intervention completion and exploring effects on cardiovascular events and mortality during a 3.5 year follow-up period. To accomplish this goal, we will randomize 120 obese adults (BMI ?30 kg/m2 or waist circumference >102 cm in men and >88 cm in women) aged 55-75 years with CHD to 6 months of cardiac rehabilitation (Rehab) alone or to cardiac rehabilitation plus a behavioral weight loss intervention (Rehab+WL) that elicits body fat loss. The specific aims are to determine the effects of Rehab+WL vs. Rehab alone on exercise capacity as measured by the 6-minute walk (primary aim); indices of arterial wave reflection (aortic augmentation index, reflection magnitude, late systolic load), arterial stiffness (carotid-femoral pulse wave velocity), peak aerobic capacity (VO2 peak), quality of life (SF-36), body composition (by DXA), body fat distribution (by CT), CHD risk factors (lipids, glucose, blood pressure), and inflammation (secondary aims); and a composite endpoint including all- cause mortality and cardiovascular events during up to 3.5 years of follow up (exploratory aim). Determining whether novel interventions designed to promote meaningful weight loss and sustained behavioral changes can improve outcomes and long-term prognosis in CHD patients with obesity has the potential to significantly advance the field and lend additional support for health care policy changes focused on obesity. Confirmation of our hypothesis will provide strong impetus for adding a formal weight loss program to cardiac rehabilitation guidelines and implementing new models of care for CHD patients with obesity.